Supplemental Digital Content 1

(1)

Sex, Occlusion time Adembri C.

Anesthesiology 2006;104:80

Rats, Sprague Dawley (S-D), adult male, permanent middle cerebral artery occlusion (MCAO)

Propofol 100 mg.kg^-1 intraperitoneal (i.p.) Treatment

during/after ischemia

Lipid emulsion Neurological deficit score (NDS), Infarct volume (IV) 24 h post-

ischemia/reperfusion (I/R)

Treatment decreased IV and NDS

Decrease in mitochondrial swelling

Bhardwaj A. Stroke 2001;32:1920

Rats, Wistar, adult male. 2 h MCAO

Exposure to halothane (1-2%, 1 or 8 h) exposure 24 h pre-I/R. Treatment before ischemia

Propofol (30 mg.kg^-

1.h^-1, 1 or 8 h)

IV: 22 h post-I/R Treatment with halothane reduced IV

Short exposure halothane better than propofol, independent of blood flow effects Bleilevens C. Exp

Brain Res 2013;224:155

Isoflurane 1.5-2%

during surgery and ischemia. Treatment during/after ischemia

Anesthesia for ischemia ketamine (100 mg.kg^-

1)/xylazine (10 mg.kg^-1) i.p.

NDS, IV 24 h post- I/R

IV, NDS reduced and survival improved by isoflurane

Isoflurane

decreased edema and inflammatory responses

Chang ML. Neurosc Lett 2002;322:137

Rats, Wistar, adult male. 90 min MCAO

Ketamine 200 mg.kg^-

1 i.p. ± nicotinamide 500 mg.kg^-1.

Treatment

Isoflurane, 5% in 70% nitrous oxide (N2O), 30% oxygen (O2)

IV 6h or 24 h post I/R

IV reduced with combination of ketamine and nicotinamide

Nicotinamide may prevent energy depletion.

(2)

Chaparro E.

Journal of Enzyme Inhib Med Chem 2013;28:1324

Rats, S-D, adult male, permanent MCAO

Isoflurane, propofol

± intraperitoneal caspase inhibitor days 0, 1,7 post-I/R.

Treatment

No injections, isoflurane anesthesia for surgery

NDS, IV 14 d post I/R

Caspase inhibition reduced injury, anesthetics did not

Reduction of caspase-mediated apoptosis

Chen L. Acta Anaesthesiol Scand 2008;52:413

Rats, S-D, adult male.

permanent MCAO

Propofol , 80 mg.kg^-

1, i.p. added to isoflurane maintenance.

Treatment

Anesthesia for ischemia: Isoflurane 1.5-2%

NDS, IV: 3, 6, and 24 h post-I/R

Propofol reduced NDS, infarct volume and apoptosis

Time-response experiment.

Enhanced

expression of anti- apoptotic B-cell lymphoma-2 (Bcl- 2)

Chen Y. Br J Anaesth 2015;114:327

Rats, S-D, adult male. 1 h MCAO

Sevoflurane 2.7/97%

O2 vols% for 45 min 1h before I/R.

Treatment before ischemia

97% O2 vols%.

Anesthesia for MCAO – 3%

Sevoflurane

NDS, IV 1, 7 d post- I/R

Treatment reduced NDS, IV at 1, 1 and 7 d post-I/R

respectively,

Protein kinase B (Akt) activation

Codaccione J-L.

Sevoflurane 2.7% in 30% O2/ 70%N2

before I/R, ischemia awake. Treatment before ischemia

Anesthesia:

Sevoflurane (3%), removed during ischemia

NDS, IV: 3, 7, 14 d post-I/R

Sevoflurane reduced NDS and IV at 3 d but not 7 or 14 d post I/R

Sevoflurane decreased

ischemia-induced apoptosis for

(3)

recovery times up to 7 d post-I/R David HN. J Cereb

Blood Flow Metabol 2003;23:1168

Rats, S-D, adult male. 90 min MCAO

Xenon 50%, 75%, N2O 75%. Treatment during/after ischemia

N2O 75%, Air IV 24 h after I/R Both Xenon and N2O reduced IV

Dong, P.

Neuroscience 2014;275:2

Rats, Fisher 344, adult male - young (4 months), old (24 months), 2 h MCAO

Sevoflurane 2.6% for 15 min at the start of reperfusion.

Treatment

Anesthetic for ischemia: Chloral hydrate (300 mg.kg^-

1)i.p.

NDS,IV 24 h after I/R

Sevoflurane improved NDS, IV, edema formation and apoptosis in young but not aged subjects

Aging-associated decreases in expression of anti- apoptotic

molecules may explain lack of neuroprotection.

Haelewyn B. Br J Anaesth

2003;91:390

Halothane or desflurane during ischemia, Treatment during/after ischemia

Awake during ischemia

IV 24 h after I/R Both desflurane and halothane reduced IV

Homi HM.

Mice C57BL/6, adult male, 1 h MCAO

70% Xenon.

Treatment

70% N2O NDS, IV 24 h after I/R

70% Xenon reduced NDS, IV

(4)

Inoue S.

Rats, Wistar, adult male 1 h MCAO

Isoflurane 1.8%

maintained during ischemia. Treatment during/after ischemia

Isoflurane

discontinued during ischemia “Awake controls”

NDS, IV evaluated 14 d after I/R

Isoflurane did not reduce NDS or IV.

Caspase inhibition reduced IV, NDS in both awake and isoflurane-treated subjects

Inoue S. Anesth Analg

2006;102:1548

Rats, Wistar, adult male 1 h MCAO

Isoflurane 1.8%

Isoflurane

discontinued during ischemia “Awake controls”

Neurologic scores, i IV evaluated 14 d after I/R

Isoflurane

decreased NDS and IV.

Intraventricular a caspase 8 inhibitor enhanced

neuroprotection Jeong S. J

Neurosurg Anesthesiol 2012;24:51

Rats, S-D, adult male. 90 min MCAO

Remifentanil, 5 μg.kg^-1.min^-1 ± opioid receptor antagonists.

Treatment

Sevoflurane ± opioid receptor antagonists

NDS, IV 1d post-I/R Remifentanil decreased both NDS and IV

Remifentanil reduced

overexpression of inflammatory mediators: tumor necrosis factor (TNF-α) Ji F-T. Mol Med

Reports 2015;12:2049

Propofol, 20 or 40 mg.kg^-1.hr^-1, Treatment

Anesthesia for surgery – halothane 1.3%/70% N2O

NDS, Evan’s blue extravasation, brain water content

Propofol decreased NDS, brain water and Evan’s blue extravasation

Metalloproteinase (MMP) activity and aquaporin (AQP) expression attenuated by propofol

(5)

Kapinya KJ.

NeuroReport 2002;13:1431

Mice, C57BL/6, adult male 1 h MCAO

Exposure to 0.8- 1.4% isoflurane . Treatment before ischemia

Preconditioned with air.

IV 48 h after I/R IV reduced by isoflurane

Neuroprotection abolished with mild hypoxia or iron chelator. Dose- response relationship.

Kawaguchi M.

Rats, Kyoto Wistar, adult male, 1 h MCAO

Isoflurane 1.8%

Isoflurane for

procedure, I/R awake

Neurologic scores, infarct volume; 2, 14 d after I/R

Isoflurane reduced IV at 2 but not 14 days after I/R

Concern that effects of

isoflurane may be transient.

Kawaguchi M.

Anesth Analg 2004;98:798

Rats, Wistar- Kyoto, adult male. 70 min MCAO

Isoflurane 1.8%

Isoflurane for procedure, I/R awake.

IV, # of apoptotic neurons 7 h, 1,4 or 7days post-I/R

Isoflurane reduced IV in the acute but not the delayed stage after I/R

Isoflurane

decreased apoptotic neuron count in the acute but not the delayed stage after I/R

Kitano H. J Cereb Blood Flow Metabol 2007;27:1377

Mice, young &

middle aged male and female, protein kinase B (Akt) + and Akt –

Exposure (4h) to isoflurane 1% in O2- enriched air 24 h before I/R. Treatment before ischemia

Exposure (4h) to O2- enriched air 24 h before I/R.

Isoflurane for surgery, awake during ischemia

NDS, IV 22 h post I/R

Treatment

decreased injury in young, middle- aged males, increased injury in young females, no

Neuroprotection not observed in Akt- male mice.

(6)

strains, 2 h MCAO

effect in middle- aged females.

Kotani Y. J Cereb Blood Flow Metabol 2008;28:354

Mice, ddY, adult male

Propofol 1, 5 or 10 mg.kg^-1 i.p. ± disodium edetate (EDTA), Treatment before ischemia

1-1.5% Isoflurane in 60% nitrous oxide

NDS, IV 24 h or 7 d after I/R

Propofol decreased IV but not NDS

Addition of EDTA increased

neuroprotection possibly by zinc chelation Lee J.

Anesthesiology 2008; 108:1055

Rats, S-D, adult male 90 min MCAO

Exposure to

isoflurane 2% for 1 h at the start of

reperfusion.

Treatment

No exposure to isoflurane during reperfusion – awake ischemia and awake reperfusion

NDS, IV 24 h after I/R

Treatment during/after ischemia improved both outcomes.

Block of mitochondrial ATP-sensitive K⁺ channels

(mitoKATP) abolished neuroprotection.

Lee J. Neurochem Res 2013;38:2276

Rats, S-D, adult male, 1 h MCAO

Propofol 0.1 ml.kg^-

1.min^-1for 1 h from the start of

reperfusion Treatment

Anesthesia for surgery was zoletil (30 mg.kg^-1)/xylazine (10 mg.kg^-1) i.p.

Controls received saline infusion

NDS, IV, blood brain barrier (BBB)

integrity, cerebral edema 24h after I/R.

Treatment decreased IV and NDS, cerebral edema and improved BBB integrity

Treatment decreased the expression of AQP, MMP, and

hypoxia-inducible factor(HIF) -1α Li B. Int J Devl

Rats, S-D, adult male 1 h MCAO

Exposure to 2.6%

sevoflurane for 1 hour at onset of reperfusion.

Surgery, Ischemia under pentobarbital

Infarct volume, neurobehavioral scores 72 h after I/R

Treatment reduced NDS and infarct size

Effect may involve Akt

(7)

Treatment

anesthesia (35 mg.kg^-

1 i.p.) Li D. PLoS ONE

2013; 8:e73334

Rats, S-D, adult male 2h MCAO

Normal and diabetic animals exposed to 2.6% sevoflurane for 15 min at the start of reperfusion.

Treatment

Ischemia performed under chloral hydrate anesthesia (300 mg.kg^-1)

IV NDS, 24 h after I/R

Treatment reduced NDS and IV in normal but not diabetic Rats.

Decreased mitoKATP channel in diabetic rats interferes with neuroprotection.

Li H. Neurobiol Dis 2013;54:216

Exposure to

isoflurane (2 %) for 60 minutes

immediately after MCAO. Treatment during/after ischemia

Anesthetized for MCAO with isoflurane, but awake during I/R

NDS and IV

determined 1,2 and 4 weeks after I/R

Improved outcomes in isoflurane- treated persisted for 4 weeks

Treatment during/after ischemia reduced nuclear

transcription factor (NF-ΚB) activation and interleukin 1β (IL-1β) and

interleukin-6 (IL-6) production in the penumbra Li L. Eur J

Pharmacol 2008;586:106

Rats, S-D, adult male permanent MCAO

Exposure to

isoflurane 2% for 30 min, 24 h before I/R.

Anesthetized for MCAO with isoflurane, but awake during I/R

NDS, IV determined 24 h after I/R

Treatment

decreased IV, NDS

Treatment increased Bcl-2 expression, and reduced

mitochondrial

(8)

cytochrome c release Li L. Neuroscience

2009;164:497

Exposure to

isoflurane (1.1,2.2%) or desflurane

(6,12%) for 30 min immediately before MCAO. Treatment before ischemia

Anesthetized for MCAO with isoflurane or desflurane

NDS, IV volumes determined 24 h and 4 weeks after I/R

Isoflurane

decreased NDS, IV at both assessment times. Desflurane did not.

Dose-response relationship.

Increased Bcl-2 expression associated with neuroprotection

Li L. Brain Res Bull 2013;98:23

Mice, wild-type and excitatory amino acid receptor- deficient (EAAT3 ) adult male, 60 or 90 min MCAO

Exposed to 1.5%

isoflurane for 30 minutes, with a 30 min washout period before the onset of surgery. Treatment before ischemia

Surgery performed under isoflurane anesthesia, for ischemia/reperfusion animals were awake

NDS, IV 24 h after I/R.

Treatment

decreased NDS and IV in wild-type mice but not in EAAT3 mice

EAAT3 deficient mice did not show neuroprotection at either 60 or 90 min ischemia time.

Downstream event includes Akt activation Li Q. Brain Res

2012;1451:1

Exposure to

isoflurane (1.4 %) for 30 minutes

immediately after MCAO. Treatment during/after ischemia

Anesthetized for MCAO with isoflurane

Isoflurane Treatment during/after ischemia reduced IV and NDS

Possible involvement of HIF-1α and nitric oxide synthase (NOS) in neuroprotection

(9)

Li X.

Rats, S-D adult male 120 min MCAO

Exposure to 2%

sevoflurane for 2 h, 2 hour washout before I/R Treatment before ischemia

Surgery, I/R under pentobarbital

1 i.p.)

Treatment

Treatment decreased the ischemia-induced upregulation of astrocyte apoptotic signalling pathways Liang C. J

Neurosurg Anesthesiol 2013;

25:311

Rats, S-D adult male, 90 min MCAO

Propofol infusion (10,20,50 mg.kg^-1) for 30 min at start of reperfusion.

Treatment

Ischemia/reperfusion done under

pentobarbital

1, i.p.)

Treatment

decreased NDS, IV and apopotosis.

Treatment upregulated expression of the antioxidant heme oxygenase-1

Liu Y. Can J Anesth 2006;53:194

Exposure to 1.5%

isoflurane for 1 h before I/R.

Ischemia/reperfusion under isoflurane anesthesia

Treatment

decreased NDS and IV

Ischemic tolerance attenuated by adenosine A1

receptor antagonist

Lückl J. Brain Res 2008;1191:157

Isoflurane

(1%)/nitrous oxide during I/R.

Treatment

α-chloralose NDS at 24, 72 h post-I/R; IV at 72 h post-I/R

Isoflurane

decreased IV, NDS similar

(10)

Lückl J.

Post-hoc comparison of isoflurane/nitrous oxide Treatment during/after ischemia

Halothane/N2O IV 72 h post-I/R No difference in IV between anesthetics

Post-hoc collection of data from pilot studies. Anesthetic comparison

accidental Maud P. Biomed

Res Int 2014; ID 802539

Rats, Wistar adult male 60 min MCAO

Isoflurane (2%) for ischemia. Treatment during/after ischemia

Chloral hydrate (300 mg.kg^-1) for ischemia

IV 24 h post-I/R No difference in IV between anesthetics

Mayanagi K. Brain Res 2007;1168:106

Isoflurane 1.7% for ischemia. Treatment during/after ischemia

Halothane 1.2% for ischemia.

IV determined immediately

No difference in IV between anesthetics

Manipulation of mitoKATP channel opening alters neuroprotection Pittman JE.

Rats, Wistar, adult male 75 min MCAO

Propofol (total dose:

291±45 mg.kg^-1)).

Treatment

Pentobarbital (total dose:135±12 mg.kg^-1

NDS, IV 7 d post-I/R No difference in IV or NDS between anesthetics

Equal metabolic suppression by EEG criteria

Qiu C. Neural Regen Res 2013;8:2126

Rats, S-D adult male, permanent MCAO

Sevoflurane 2.4% for 15,30,60 or 120 min 50 min before I/R.

Air IV, NDS 24 h after

I/R

Treatment for 15, 30, and 60 min reduced IV but not NDS

Time-dose study

(11)

Ritz M-F. Intern J Neurosci

2006;116:191

Rats, Wistar, adult male 90 min MCAO

Isoflurane 1.5%

during I/R.Treatment during/after ischemia

Pentobarbital 50 mg.kg^-1 during I/R

IV 24 h post-I/R, glutamate and taurine (EAA)

concentrations

No difference in IV between anesthetics

Isoflurane prevented the ischemia-induced increase in EAA’s Sakai H.

Rats, Wistar adult male 50 or 80 min MCAO

Exposure to isoflurane 1.5%

during ischemia.

Treatment

Anesthetic removed – ‘awake’ controls

NDS, IV 2 weeks and 8 weeks post-I/R

Treatment reduced NDS and V persisting to 8 weeks post-I/R

Block of mitoKATP did not alter outcomes in any group

Sarraf-Yazdi S.

Rats, Wistar adult male, 75 min MCAO

Exposure to low- dose isoflurane (0.7%) during ischemia ±

dizocilpine (1 mg.kg^-

1) i.p. 30 min before MCAO.

Anesthetic removed – ‘awake controls

NDS, IV 1 week post-I/R

Isoflurane did not reduce NDS or IV compared to awake or to dizocilpine- treated subjects

Comparison with glutamate receptor blocker

Schmid-Elaesser R.

J Neurol Sci 1999;162:14

Rats, S-D, adult, 120 min MCAO

Low-and high-dose pentobarbital by EEG criteria Treatment

Halothane IV immediately after ischemia

Pentobarbital reduced IV

No difference between doses

(12)

Shi H. CNS Neurol Disord Drug Targets 2013;12:381

Rats, S-D, adult male, 120 min MCAO

Exposure to 1 MAC (2.4%) sevoflurane in air for 30 min per day on 4 consecutive days. Treatment before ischemia

Air

Isoflurane (1-2%) to both groups during ischemia.

NDS, IV 24 and 48 hrs after I/R

Treatment

Treatment reverses suppression of anti- apoptotic Bcl-2 pathways;

microRNA’s involved Shi S-s. Neurochem

Res 2014;39:793

Rats, S-D, adult male, permanent MCAO

Propofol 10 or 50 mg.kg^-1 ; Treatment during/after ischemia

Chloral hydrate (300 mg.kg^-1 i.p.)in all groups

NDS, IV 24 h after ischemia

NDS and IV reduced by propofol

Attenuation of overexpression of inflammatory mediators: TNF-α, NF-κB,

cyclooxygenase-2 (COX-2)

Shu L. Neurochem Res 2012;37:49

Mice, BABL/c, adult male, Permanent MCAO

Propofol or ketamine 25, 50, 100 mg.kg^-1, Treatment

Pentobarbital (60 mg.kg^-1 i.p.)

NDS, IV 6 h after MCAO

NDS, IV decreased by both propofol and ketamine

Inhibition of cAMP response element- binding protein (CREB) by both drugs. Dose response study Soonthon-Brant V.

Rats, Wistar- Kyoto adult male, 90 min MCAO

Isoflurane 1 MAC (1.1%) or

Anesthetic removed – ‘awake’ controls

IV 1 week after I/R Isoflurane, but not fentanyl decreased IV

High dose fentanyl, no detrimental effect

(13)

Fentanyl 50 µg.kg^-

2.hr^-1Treatment during/after ischemia Sun H. Brain Res

2008;1194:73

Ischemia/reperfusion under isoflurane 2%/30% air Treatment

Ketamine/xylazine (100/15 mg.kg^-1 i.p.)

NDS,IV 24 hrs after I/R

No difference between anesthetics

IV, NDS greater in alcohol-fed animals

Sun M. Scientific Reports

2015;5:11445

Thirty min exposure to isoflurane 2%, 24 hours before I/R Treatment before ischemia

Chloral hydrate NDS, IV 24 hr after I/R

Treatment decreased IV and NDS

Decreased activation of NF- κB pathway, Toll- like receptor-4 (TLR-4); decreased microglial

inflammation Taheri S. Brain Res

2014;1586:173

Rats, Wistar, adult male, 90 min MCAO

Ischemia/reperfusion under 2% isoflurane.

Treatment

Anesthetic removed – ‘awake controls

IV measured with magnetic resonance imaging 0-12d after I/R

IV peaked from 24-72 h post-I/R, defining the acute phase

Treatment enhanced

expression of HIF- α and vascular endothelial growth factor (VEGF)

(14)

Tong L. Br J Anaesth 2014;113:157

Sevoflurane 2.7% in oxygen for 1 h, with 1 h washout before MCAO. Treatment before ischemia

97 % oxygen NDS 24,48, 72 h after I/R, IV 72 h and 1 week after I/R

Treatment

Neuroprotection attenuated by knockdown of a two-pore domain K+ channel (K2P TREK-1)

Tong L. Mol Neurobiol 2015;51:1221

Isoflurane 2% 1h.d^-1 x 5 d before I/R;

Treatment before ischemia ± small interfering RNA (siRNA) for ubiquitin (Ubc9) conjugase . Treatment before ischemia

98% O2 NDS at 1, 2, 3,7, and 14 d post I/R; IV at 3,7, 14 d

Treatment reduced NDS at all times, IV at 3d and 7 d

Ubc9 expression increased by Treatment, neuroprotection abolished by siRNA knockdown of Ubc9

Wang H. Front Biosci 2011; E3:604

Exposure to

sevoflurane (1.2% or 2.4%)in air for 30 min on 4 consecutive days , ending 1 d before MCAO Treatment before ischemia

Ambient air NDS, IV 72 h after I/R

Both doses of sevoflurane

Neuroprotection associated with suppression of NF- ΚB, P38 mitogen- activated kinase (MAPK)

(15)

Wang H. J Neurochem 2011;119:210

Thiobutabarbital 100 mg.kg^-1 i.p.

Propofol, 20 mg.kg^-

1.h^-1, for 4 h beginning at the onset of reperfusion.

Treatment

Intralipid® infusion

Morris water maze test at 14, 28 d post- I/R, infarct size 1, 14 and 28 d after I/R.

NDS only used to exclude uninjured animals, not reported

Propofol improved maze performance and decreased IV at all times

Neuroprotection associated with glutamate receptor dynamics

Wang H. Brain Res 2015;1597:210

Propofol 20 mg.kg^-

1.hr^-1 during ischemia and 1 h of

reperfusion.

Treatment

Saline infusion

NDS 24 h post-I/R Treatment decreased NDS.

Treatment during/after ischemia enhanced the expression of K⁺ - Cl^- co- transporter 2 (KCC2) Wang H-y. Brain

Res 2009;1297:177

Thiobutabarbital + Propofol (10,20,35 mg.kg^-1.hr.^-1) Treatment

Treatment with 10 and 20 mg.kg^-1.h^-1 but not 35 mg.kg^-

1.h^-1 decreased IV and NDS

Dose-response relationship, Phosphoinositide- 3-kinase (PI3K) – Akt pathway inhibition attenuated neuroprotection

(16)

Wang J-K. Brain Res 2010; 1357:142

Exposure to sevoflurane 0.5, 1 and 1.5 MAC in O2

for 30 min starting 90 min after MCAO.

Treatment

Chloral hydrate 350 mg.kg^-1 i.p.; O2 for 30 min starting 90 min after MCAO

Neurologic outcome, Infarct volume 22 h after I/R

Treatment with 1 and 1.5 MAC isoflurane decreased IV and NDS

Dose-response relationship, PI3K inhibition

attenuated neuroprotection.

Wang J-K. Neurol Res 2015;37:77

Exposure to

sevoflurane 1 MAC in O2 for 30 min starting 90 min after MCAO. Treatment during/after ischemia

Chloral hydrate 350 mg.kg^-1 i.p.; O2 for 30 min starting 90 min after MCAO

Neurologic outcome, Infarct volume 24 h after I/R

Treatment reduced IV and NDS

Block of mitoKATP

channel and mitochondrial permeability pore attenuated neuroprotection.

Wang L. J Cereb Blood Flow Metabol 2008;28:1824

Mice, C57BL/6 young adult female, 120 min MCAO

Exposure to 1 % isoflurane/O2-

enriched air for 4 h, 1 d before I/R

Treatment before ischemia.

No exposure NDS, IV 22 h after I/R

Treatment reduced IV volume in ovariectomized mice

Role of estrogen, including estrogen receptor deficient subjects

Wang Z.

NeuroRehabilitation 2014;35:825

Rats, S-D, adult male, 120 min MCAO Treatment

Propofol (10 mg.kg^-

1.h^-1),

dexmedetomidine (4 μg.kg^-1.h^-1)

intravenously alone

All groups received chloral hydrate (350 mg.kg^-1)

NDS, Morris water maze test

Both drugs reduced NDS and the combination had additive effects

Neuroprotection was associated with decrease in TNFα and IL-1β

expression; increae

(17)

or in combination 20 min before and during I/R Treatment during/after ischemia

in expression of Akt

Warner DS.

Rats, Wistar, adult male, 90 min MCAO

Pentobarbital low or high dose measured by EEG. Treatment during/after ischemia

Pentobarbital 40 mg.kg^-1 i.p.

Ischemia/reperfusion awake

NDS, IV 7d post I/R No difference in outcome measures between

anesthetics;

‘awake’ controls worse

Greater metabolic suppression with high dose not associated with improved outcome

Xiao Z. Mol Med Rep 2015;12:675

Isoflurane 2%/Nitrogen(N2) 40%, O2 60% for 1 h, 1 day before I/R, Treatment before ischemia.

N2 40%, O2 60% for 1 h, 1d before I/R

NDS, IV 1d post I/R Treatment before ischemia decreased NDS and IV

Decreased levels of inflammatory mediators:

TLR4,Nf-κB, TNF- α

Xiong L. Chinese Med J 2003;

116:108

Isoflurane 1.5 % for 30 min/day for 5 days

Electroacupuncture (EA) under 1.5%

isoflurane for 5 days

No treatment Neurological deficit score and infarct volume 24 h after I/R

Outcomes were similar in

isoflurane-treated and control groups.

IV and NDS were decreased with EA.

EA effective

(18)

Xiong L. Anesth Analg 2003; 96:233

Rats, S-D, adult male, 120 ;min MCAO

Isoflurane (0.75, 1.5 and 2.25%) in oxygen, for 1 hour for 4 days before I/R Treatment before ischemia.

O2 NDS, IV volume 24

h after I/R

1.5%, 2.25%

isoflurane Treatment

Neuroprotection abolished by glibenclamide, a mitoKATP channel blocker. Dose response relationship Yang Q. Anesth

Analg

2011;112:931

Sevoflurane (1, 2, 4%) in O2 for 1 hour for 5 consecutive d before I/R. Treatment before ischemia.

O2 NDS, IV evaluated at

24, 48 and 72 h after I/R

NDS, IV decreased by Treatment with 2,4% sevoflurane

Neuroprotection abolished by antioxidant or free radical scavenger

Yang Q.

Mice, C57BL/6;

Conditional Notch-RBP-J knockout, adult male, 60 min MCAO

Sevoflurane (2.5%) in oxygen for 1 hour for 5 consecutive days before ischemia reperfusion.

air, O2 NDS, IV determined 72 h after I/R

NDS and IV decreased by Treatment with sevoflurane

Treatment activated the Notch

signalling pathway.

Neuroprotection was attenuated by pathway inhibition and in Notch pathway- deficient mice

(19)

Yang Z. Mol Med Rep 2014;9:843

Rats, S-D, adult male, high- and low-fat diets, 60 min MCAO

Sevoflurane 2.6% for 15 min at the onset of reperfusion .

Treatment

Chloral hydrate (300 mg.kg^-1)

Treatment

improved outcome in low fat but not high fat diet animals

Obesity associated with an impaired mitoKATP channel

Ye R. Crit Care Med 2012;40:2685

Exposure to 2.3%

sevoflurane in oxygen for 1 h, 24 h before ischemia.

Exposure to O2 for 1 h, 24 h before ischemia

NDS determined 1,3,7,14,28,42 d post-I/R. IV 3 d post- I/R

Treatment decreased IV and NDS day 7-42

Treatment associated with reduced opening of mPTP

Ye Z. Neurol Sci 2012;33:239

Exposure to 2.4%

sevoflurane in oxygen for 1h, 24 h before ischemia.

Exposure to oxygen for 1 h, 24 h before ischemia

NDS, IV evaluated 24 and 72 h after I/R

Treatment decreased IV and NDS.

Neuroprotection was attenuated by mitoKATP channel block.

Ye Z. Mol Biol Rep 2012;39:5049

Exposure to 2.4%

sevoflurane in O2 for 1h, 24 h before I/R Treatment before ischemia.

Exposure to O2 for 1 h, 24 h before ischemia

NDS and IV

evaluated 6 and 24 h after I/R

Treatment

Neuroprotection attenuated by mitoKATP channel block.

(20)

Ye Z. Brain Res 2012;1463:63

Rats, S-D adult male permanent min MCAO

Sevoflurane 2.5% for 60 min after

reperfusion . Treatment

Chloral hydrate (350 mg.kg^-1)

IV 24 h after I/R Treatment decreased IV

Treatment increased brain levels of Akt and HIF-1α

Yu H. Obesity 2014;22:2396

Mice, CD-1, adult male, 90 min MCAO Regular diet and high fat diet animals

Exposure to 1 or 2%

isoflurane in O2 for 30 min at the start of reperfusion.

Treatment

Exposure to O2 for 30 min at the start of reperfusion

Treatment decreased IV and NDS in regular diet but not high-fat diet mice

Impaired Akt signalling in high fat diet animals

Yung LM. Stroke 2012;43:199

Mice, C57BL/J;

sphingosine kinase (SPK) knockouts:

SPK1^-/-, SPK2^-/- adult males, 90 min MCAO

Exposure to 1%

isoflurane/ 30% O2

for 3 h, 1 day before MCAO Treatment before ischemia.

Exposure to air for 4 hours

Treatment

decreased NDS and IV in wild-type and SPK1^-/- but not SPK2^-/- mice

Neuroprotection abolished with a SPK inhibitors.

SPK2may be a mediator isoflurane Treatment.

Zhang Y. Molecules 2012;17:341

Sevoflurane 0.5, 1.0 or 1.5 MAC / O2 for 30 min at the onset of reperfusion

Chloral hydrate (350 mg.kg^-1 i.p.) to all groups. Exposure to

IV 24 h after I/R IV decreased at all doses of

sevoflurane

Treatment dose- dependently decreased serum

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Treatment

O2 for 30 min at the onset of reperfusion.

levels of TNF-α and IL-1β Zhao H. Brain Res

2008; 1246:158

Isoflurane 2% in 30% O2 during ischemia. Treatment during/after ischemia

Ketamine/xylazine, 80/40 mg.kg^-1i.p.

NDS, IV decreased in isoflurane group

Zhao X-C.

Neurochem Res 2013;38:530

Propofol 20 mg/kg/hr for 4 hrs beginning at reperfusion, Treatment

Chloral hydrate (350 mg.kg^-1 i.p.)

NDS determined at 1, 3, 7d post-I/R; IV at 6h, 1,3 7 d post I/R

Treatment

improved NDS and IV at all times

Expression of basic fibroblast growth factor increased by propofol

Zheng Y-Y. Anesth Analg

2008;107:2009

Propofol infusion for 15 min before I/R, .Treatment before ischemia.

Chloral hydrate (300 mg.kg^-1 i.p.) to all groups

No difference in IV, NDS

Brain water and AQP

overexpression reduced by Treatment Zheng S. Mol

Pharmacol 2004;65:1172

Rats, S-D adult male, permanent MCAO

Isoflurane 2% for 30 min 1 d before I/R.

Air NDS measured 6 h,

1,3 and 14 d post- I/R, IV measured 6 h, 1 and 3 d post I/R

Treatment reduced NDS 1d and 3 d after I/R and IV at all times post-I/R

Isoflurane induced an increase of phosphorylated p38 MAPK

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Zhou R. PLoS ONE 2013;8:e82729

Rats, S-D adult male, 120 min MCAO,

Propofol 50 mg.kg^-

1.h^-1 for 30 min at onset of reperfusion.

Treatment

Pentobarbital 50 mg.kg^-1 to all groups

NDS, IV measured 24 h after I/R

Treatment decrease NDS and IV

Decreased microglial activation in propofol group.

Zhu W.

C57BL/6 mice, adult male, 120 min MCAO

Exposure to 1.0%

Isoflurane for 4 h 24 h prior to I/R.

Oxygen-enriched air IV 24 h after I/R Treatment decreased IV.

Protective effect was androgen- dependent.

Multiple groups with hormone manipulation.

i

Abbreviations: AKT, protein kinase B; Bax, Bcl-2-like protein 4; Bcl-2, B-cell lymphoma 2; cJNK, c-Jun-N-terminal kinase; COX, cyclooxygenase; CTMP, carboxy-terminal protein; EEAT3, excitatory amino acid transporter 3; ERK, extracellular signal-related kinases; GSK-3β, glycogen synthase kinase 3-β, HES, hairy and enhancer of split; HIF, hypoxia-inducible factor, Hsp, heat shock protein; H

2

O

2

, hydrogen peroxide; ICAM, intercellular adhesion molecule; IL, interleukin; MAPK, Mitogen-activated protein kinase;

miRNA, micro RNA; MMP, matrix metalloproteinases; mPTP, mitochondrial permeability transition pore; MyD88, myeloid differentiation primary response gene 88; NDRG2, n-myc downstream regulated gene 2; NF, nuclear factor; NICD, Notch

intracellular domain; NO, nitric oxide; NOS, nitric oxide synthase; Nrf2, nuclear factor erythroid 2-related factor, NQ01, quinidine oxidoreductase 1; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; Prok2, prokineticin 2; SPK2, sphingosine kinase 2;

TIMP, tissue inhibitor of metalloproteinase; TNFα, tumor necrosis factor alpha; TREK, TWIK-related (2-pore domain) K+ channel,

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